The long-term objective of studies in this laboratory involves the elucidation of the biologic function of C-reactive protein (CRP), a major acute phase protein in man. Experimental findings have suggested that CRP may have an important role as a modulator of monocyte function. Since many monocyte activities such as the elaboration of inflammatory cytokines are of importance in normal human physiology and in the pathogenesis of disease, an interaction of CRP with these cells may have significant biologic and clinical implications. The specific aims of this proposal are to explore the interaction of CRP with monocytes, both in healthy individuals during the physiologic process of aging and in patients with chronic rheumatic diseases associated with aging, by carrying out the following studies: 1) Identification and isolation of specific CRP receptors from monocytes will be carried out using affinity chromatography. The receptor proteins will be characterized biochemically and used to identify the receptor gene. Specific anti-CRP receptor antibodies will be generated for clinical studies of CRP receptor expression. 2) The capacity of CRP to influence monocyte production of the inflammatory cytokines TNFalpha, IL-1beta and IL-6 will be explored by assessing the kinetics, factors which influence, and mechanism of this phenomenon. 3) The potential involvement of some characteristic pathways of membrane signal transduction will be assessed using established biochemical and cytofluorometric techniques following binding of CRP to monocytes. 4) The clinical implications of the CRP-monocyte interaction will be assessed using monocytes from individuals of varying ages, and using both monocytes and synovial fluid cells from patients with acute and chronic rheumatic diseases. These studies will involve evaluation of the characteristics of CRP-monocyte binding, of in vivo CRP receptor expression, and of CRP-induced cytokine production. The dramatic acute phase behavior of CRP in man suggests a biologic role for this protein in tissue injury and inflammation, physiologic events in which monocytes are known to play an important part. Studies of the interaction of CRP with monocytes should lead to a better understanding of the role of this acute phase protein in health, during the physiologic process of normal aging and in chronic inflammatory diseases.